A number of studies have been conducted in an attempt to encapsulate drugs in microparticles and nanoparticles of poly(lactic-co-glycolic acid) (which may be referred to as “PLGA,” hereinafter) or poly(lactic acid) (which may be referred to as “PLA,” hereinafter).
For example, U.S. Pat. No. 4,652,441 (Patent Document 1) describes PLGA microcapsules containing physiologically active polypeptides, and a production method thereof. Published Japanese Translation of a PCT Application No. Hei 10-511957 (Patent Document 2) describes PLGA nanoparticles for intravascular administration containing various drugs. Also, Japanese Laid-Open Patent Publication No. Hei 8-217691 (Patent Document 3) discloses a sustained-release formulation including PLGA microcapsules encapsulating water-insoluble or hardly water-soluble polyvalent metal salts of physiologically active, water-soluble peptide compounds.
However, none of the prior art patents mentions the concept of hydrophobicizing a water-soluble, non-peptide, low-molecular weight drug by a metal ion, and encapsulating the hydrophobicized drug in a PLA-PEG block copolymer or a PLGA-PEG block copolymer in which PLA or PLGA is bound to polyethylene glycol (which may be referred to as “PEG,” hereinafter).
International Patent Publication No. WO 2003/101493 (Patent Document 4) filed by the present applicant describes a preparation including drug-encapsulating PLGA or PLA fine particles that have a surfactant adhered to the surface thereof. International Patent Publication No. WO 2004/84871 (Patent Document 5) also filed by the present applicant describes a preparation including PLGA or PLA nanoparticles encapsulating a water-soluble, non-peptide, low-molecular weight pharmaceutical agent hydrophobicized by a metal ion and having a surfactant adsorbed on the surface thereof.
However, the fine particles disclosed in Patent Document 4 can encapsulate only low amounts of the drug. The particles also tend to burst at an early stage of administration and cannot therefore achieve ideal sustained-release performance. The nanoparticles disclosed in Patent Document 5 tend to accumulate in the liver when intravenously administered despite their improved encapsulation rate of drug and decreased early burst.
Block copolymers composed of poly(lactic acid) or poly(lactic-co-glycolic acid) and polyethylene glycol are described in different publications. For example, Japanese Laid-Open Patent Publication No. Sho 58-191714 (Patent Document 6) describes a block copolymer composed of polyethylene glycol, a hydrophilic polymer, and poly(lactic acid), a hydrophobic polymer. Japanese Laid-Open Patent Publication No. Hei 9-157368 (Patent Document 7) describes a purification method of a triblock copolymer including poly(lactic acid)-polyethylene glycol-poly(lactic acid).
One proposed application of block copolymers composed of poly(lactic acid) or poly(lactic-co-glycolic acid) and polyethylene glycol is in pharmaceutical compositions. For example, Japanese Patent Publication Laid-Open No. Hei 2-78629 (Patent Document 8) describes a pharmaceutical composition including a copolymer of a copolymer of lactic acid and/or glycolic acid and polyethylene glycol, with a polypeptide added thereto. Japanese Laid-Open Patent Publication No. Hei 9-151136 (Patent Document 9) describes a solution containing a protein along with a poly(lactic acid)-polyethylene glycol copolymer.
However, nanoparticles are not known that are obtained by hydrophobicizing a water-soluble, non-peptide, low-molecular weight drug by a metal ion, and reacting the hydrophobicized drug with a poly(lactic acid)-polyethylene glycol block copolymer or a poly(lactic-co-glycolic acid)-polyethylene glycol block copolymer.
Neither are drug-containing nanoparticles known that are obtained by hydrophobicizing a water-soluble, non-peptide, low-molecular weight drug by a metal ion, and encapsulating the hydrophobicized drug in nanoparticles of a poly(lactic acid)-polyethylene glycol block copolymer or a poly(lactic-co-glycolic acid)-polyethylene glycol block copolymer, and that have favorable targeting and sustained-release properties, cause reduced accumulation of the drug in the liver, and have an improved long-circulating property.
Patent Document 1 U.S. Pat. No. 4,652,441
Patent Document 2 Published Japanese Translation of a PCT Application No. Hei 10-511957
Patent Document 3 Japanese Laid-Open Patent Publication No. Hei 8-217691
Patent Document 4 International Patent Publication No. WO 2003/101493
Patent Document 5 International Patent Publication No. WO 2004/84871
Patent Document 6 Japanese Laid-Open Patent Publication No. Sho 58-191714
Patent Document 7 Japanese Laid-Open Patent Publication No. Hei 9-157368
Patent Document 8 Japanese Laid-Open Patent Publication No. Hei 2-78629
Patent Document 9 Japanese Laid-Open Patent Publication No. Hei 9-151136